Therapeutic compositions and method of preparing same



Patented Apr. 22, 1947 THERAPEUTIC COMPOSITIONS AND METHOD OF PREPARINGSAME Simon L. Ruskin, New York, N. Y., assignor to Frances R. Ruskin NoDrawing. Application September 7, 1942, Serial No. 457,598

- Claims.

The present invention relates to cevitamic (laevo-ascorbic) acidderivatives of organic amino compounds, both acid addition products andsalts and mixed addition products and salts, and partlcularly ofsulfanilic acid and 'of sulfanilamides, including sulfanilamid itselfand its N derivatives, and also those derivatives wherein one or both ofthe hydrogens of the nuclearly bound amino group are replaced by an acylor other group, including derivatives wherein the sulfonamido group issubstituted by an alkylol group, the hydroxy group being free forreaction with the cevitamic acid to form an ester.

The present application is a continuation-inpart of my pendingapplication, Serial No. 192,789, filed February 26, 1938, which issuedas Patent No. 2,294,937, on September 8, 1942.

It is a general object of the invention to improve the physiologicaland/or physical properties of organic amino compounds having therapeuticactivity and having a basic group, such as NH2 or alcoholic hydroxyl, bycombining the same with cevitamic acid to form either a true salt or anaddition compound, to eiiect a reduction in the toxicity, an improvementin the solubility, a diminishing of irritation on injection, etc.

The toxicity of sulfanilamide and its derivatives, includingsulfanilamide itself, its N'-acyl derivatives, sulfapyridine,sulfadiazole, sulfathiodlazole, sulfadiazine, etc. is well known; infact, many of the known derivatives have been producedin the attempt toreduce the toxicity of the parent sulfanilamide. It also has been foundthat where the treatment of, for example, open wounds required both asulfanilamide drug and an alkaloid anaesthetic, such as novocaine, thelatter acts antagonistically toward the bactericide, therebyconsiderably reducing its effectiveness.

I have found that by combining various therapeutic agents containing anamino group with cevitamic or ascorbic acid, either to form an ester (asby reaction with an alcohol group) or an addition compound, or both,products of improved properties are obtained. These improvements consistgenerally in a reduced toxicity, an increased solubility, theelimination or reduction of irritating action on the tissues, and in thecase of anaesthetics, like novocaine, the suppression of the antagonismtoward sulfamlamide drugs. My improved compounds are of particular valuebecause they have associated or chemically incorporated therein asubstance, namely, cevitamic acid, which is a normal component of theblood and of body tissues, so that the modification of the knowntherapeutic agents does not involve the introduction of still anotherradical foreign to the animal organism. The combination of the normallytoxic sulfanilamides with cevitamic acid either in the form of acidaddition products, or of esters by reaction with an alcohol hydroxylgroup introduced into the sulfanilamide compound, as by substitution ofN with an alkylol group, or in both ways, thus involves a modificationof the therapeutic agent which makes it more easily tolerated by theanimal body.

The detoxicating action of cevitamic acid on the sulfanilamides isprobably the result of the formation of a larger molecule withpronounced serum protein-combining power. This combining power with theserum protein permits a greater rate and degree of absorption of thetherapeutic agent. Pick and his co-workers have shown that the toxicityof a substance introduced into the blood stream is inverselyproportional to its ability to form serum protein complexes, andsubstances that do not form the serum protein complexes are toxic andare usually excreted in the uncombined form. This is one of theunderlying difliculties with sulfonamide compounds, and in the processof excretion, they cause considerable kidney damage. The cevitamat(ascorbate) radical both increases the utilization of the sulfonamidecompound and acts as a protective mechanism in its excretion.

The following examples illustrate several methods of manufacturing theimproved compounds in accordance with the invention:

EXAMPLE 1 Preparation of acetylsulfanilyl cevitamic acid 7 g. mol)cevitamic acid were dissolved under cooling "with ice in 25 cc. dryPyridine. The solution was then treated slowly under stirring andcooling with 10 g. /100 mol) of acetylamino benzene sulfochloride, carebeing taken to keep the reaction temperature at about 50 C. The reactionmixture was then placed on ice over night. The following day it wastreated with excess ether. A heavy oil precipitated which turned to anamorphous semi-solid on being further washed with ether. The last tracesof pyridine were removed in a vacuum desiccator at room temperature. Theproduct showed no tendency to crystallize. It was soluble in water andalcohol, and insoluble in chloroform, acetone, benzene and ethylacetate. The product was taken up in 50 cc. absolute ether and treatedunder stirring with 2 equivalents of sodium ethoxide in 100 cc. absolutealcohol. The second equivalent of sodium ethoxide was added because ofthe py- 3 ridine hydrochloride present. An orange colored precipitatewas obtained which became flltcrable on standing in the ice chest overnight. Yield of sodium salt: 11 g.

Exmrn: 2

Preparation of sulfanilamide cevitamate 17.2 g. (1% mol) sulfanilamideand 17.6 g. (1% moi) oevitamic acid were well mixed and then 75 cc. drymethyl alcohol were added. On heating to the boiling point, completesolution took place with the formation of a deep yellow color. The warmsolution was then treated under stirring with 150 cc. chloroform.Afcrystalline precipitate formed which was filtered off after standingin the ice chest over night. Yield 33 g. or 95% theory.

To determine the amount of a oevitamic acid present the salt wastitrated with 0.1N iodine solution.

Mg. oevitamic acid in 200 mg. salt: 105 mg. cevitamic acid found, 101mg. oevitamic acid theory.

EXAMPLE 3 Preparation of sulfanil-ethanolamide monoascorbate 47 g. Amol) acetyl sulfanil chloride were slowly added under stirring to 24.5g. mol) ethanolamine dissolved in 100 cc. water, care being taken tokeep the reaction temperature around 40 C. At the end of th reaction athick paste was obtained which was allowed to stand on ice a few hours,and then filtered. Yield 51 g. or 98%. The crude product was dissolvedin a mixture of 25 cc. water and 50 cc. 5N sulfuric acid, and theresulting solution was then heated on a water bath for three hours. Thedarkened acid solution was then neutralized to a pH of about 10 with 30%sodium hydroxide and allowed to stand on ice over night. At this point aheavy oil was obtained which crystallized on standing in the ice chestover night. The following day the resulting sulfanil-ethanolamide wasfiltered oiT and washed with a little cold water. It was purified byrecrystallizing twice from 10 cc. boiling water to which animal charcoalhad been added. At the end of the second purification the productprecipitated as crystals. Yield 17 g. or about 40% of theory.

Analysis: N=12.61% found, 12.96% theory.

The reactions may be represented as follows:

Nnoocm 1111100011.

+ HCl-NHzCHzCHaOH SOzCl 2HzNCH CHzOH SOgNHCHgCHgOH NHCO CH5 NH;

1 SOzNHCHzCHzOH H2304 SOgNIICHzCHzOH 2.2 g. /1ou mol)sulfanil-ethanolamide and 1.8 g. 100 mol) ascorbic acid were dissolvedin cc. dry methyl alcohol and boiled on a water bath until crystalsbegan to show in the hot solution.

The reaction mixture was then treated with 35 cc. chloroform and allowedto stand on ice over night. The following day pale yellow crystals of 4the mono-ascorbate were filtered 01! and washed with chloroform. Yield3.8 g. or 95% theory.

To determine the amount of ascorbic acid present the salt was titratedwith 0.1N iodine solution.

Mg. ascorbic acid in 200 mg. salt: 92.4 mg. found.

89.0 mg. theory.

EXAMPLE 4 Preparation of sulfanil-ethanolamide di-ascorbate 2.2 g. /l00mol) sulfanil-ethanolamide and 3.6 g. /ioo mol) ascorbic acid weredissolved in 10 cc dry methyl alcohol and boiled (with cover) on a waterbath until crystals began to show in the hot solution. The reactionsolution was then treated with cc. chloroform and allowed to stand onice over night. The following day dark yellow crystals of thedi-ascorbate were filtered off and washed with chloroform. Yield 5.2g.or 90% theory.

To determine the amount of ascorbic acid present, the salt ester wastitrated with 0.1N iodine solution.

Mg. ascorbic acid in 200 mg. salt: 127.6 mg. found,

124.4 mg. theory.

EXAMPLE 5 Preparation of strychnzne ascorbate 33.4 g. strychnine and17.6 g. mol) ascorbic acid were warmed with 250 cc. absolute methylalcohol, and the resulting solution concentrated to about 150 cc. It wasthen treated with about 1000 cc. acetone which were slowly added understirring and cooling. An amorphous precipitate was obtained whichhardened on standing in the ice chest over night. Yield 41 g. or nearlyThe product is light yellow and soluble in its own weight of water. 1

EXAMPLE 6 Novocaine ascorbate 23.6 g. 6 mol) novocaine and 17.6 g. (1 6mol) ascorbic acid were warmed with about 200 cc.

absolute methyl alcohol until solution was complete. The resultingsolution was then slowly treated under stirringand cooling with 500 cc.chloroform or acetone. A yellow precipitate was obtained, which hardenedon standing over night in the ice chest. Yield 40 g. or almostquantitative. The cevitamates of cocaine and atropine may be similarlyprepared.

In certain of the above reactions, as in the reaction betweensulfanilamide and ascorbic acid, a small proportion of zinc chloride maybe employed as catalyst in the salt or ester formation.

That some sort of chemical combination takes place between the aminocompounds above described and oevitamic acid is evident, for example,from the fact that in th case of sulfanilamide cevitamate, greatersolubility in methyl alcohol is obtained than is possessed either bysulfanilamide or by cevitamic acid. As this product is the salt or arelatively weak acid and relaamount of cevitamic acid, the solubility ofsulfa-- nilamide in water is increased from about 0.8% to about 1.2%.This increase in solubility with simultaneous reduction in toxicitygreatly enhances the therapeutic value of the sulfanilamide.

While in certain of the above examples I have described the use of Nacetyl derivatives, such acetylated' compound was presented only by wayof example; for other acyl groups may be substituted in the para-aminogroup, such as propionyl, valeryl, benzoyl, and the like. Where it isdesired to form the ester of a sulfonalkylolamide compound withcevitamic acid while keeping the para-amino group unsubstituted, thecorresponding para-nitro compound may be used as starting material andthe para-nitro-benzenesulfonalkylolamide cevitamate then converted to'the corresponding para-amino compound by careful reduction, asby meansof activated hydrogen in the manner/well understood in the art.

In place of the ethanolamine, other alkylolamines may be used, such aspropanolamine; butanolamine, as well as their isomers and the higheralkylolamines.

Heterocyclic compounds having a reactive amino group are also suitablefor the production of valuable therapeutic compounds. For instance, onemay employ the 2.6 diamino 2-ethyl pyridine, which possesses anaestheticproperties, and bring the same into reactive contact with cevitamic acidto cause the formation of an amino-ethyl-pyridine-amino cevitamatehaving considerably improved properties. Other compounds of analogouscharacter and having the pyridine or quinoline nucleus may be employedin this reaction.

Many di-azo compounds are known which have found application as valuableanti-bacterial agents and have aryl as Well as heterocyclic groups maybe combined in accordance with the present invention. As typical of suchcompounds one may take the 3.6 diamino 2-methyl 5-phenylazo pyridine andcombine the same with cevitamic acid as above explained. Other compoundsof the azo type having two heterocyclic radicals are also applicable tothe present invention; for example, the 2.6 diamine 3-pyridylazopyridine may be-coupled wtih the cevitamic acid to give bactericidalcompoundsof improved value. Also available are similar compounds havingsubstituent groups in place of one or more of the free hydrogens on therings, such as halogen, hydroxy, alkoxy, alkyl, aryl, and the like.

From the above it will be seen that a very large variety of therapeuticcompounds of diverse characters are suitable for combination withcevitamic acid, forming compounds of enhanced value. While the characterof the compounds may vary widely, it is essential that there be presentan amino group capable of combining with an acid group under theconditions stated above or under other conditions well known to theskilled chemist; or else, an alkylol group having a free hydroxylcapable of reacting with cevitamic acid.

The dosage of my improved compounds can be made the same as thecorresponding known compounds; however, because of generally improvedtherapeutic ratio, somewhat lower dosages may be relied on. My improvedproducts can be administered orally or parenterally, or applied to openwounds, just like the corresponding known compounds.

Although I have described my invention by setting forth several specificembodiments thereof, it is not limited to the details set forth above. Iam not to be limited to the specific compounds described, as'othercompounds of analogous character may be formed wherein the reactiveamino group is attached to organic radicals of alkyl, aryl,

'aralkyl, heterocyclic and mixed types.

I claim:

1. Method of preparing sulfanilyl-ethanolamide ascorbate which comprisesheating sulfanilyl-ethanolamide with ascorbic acid in dry methylalcohol, adding thereto an organic solvent miscible with the alcohol butin which the ascorbate is relatively insoluble and thereafter separatingthe precipitated ascorbate.

2..Method according to claim 1, wherein the added organic solvent ischloroform.-

3. A therapeutic preparation comprising a compound of ascorbic acid anda sulfanilalkylolamide.

4. A therapeutic preparation comprising a compound of ascorbic acid anda sulfanilethanolamide.

5. The product obtained by the reaction of a member of the groupconsisting of sulfanil-N alkylolamides and the N -acyl derivativesthereof with ascorbic acid. 6. The product obtained by the reaction of amember of the group consisting of sulfanil-N ethanolamide and the N-acy1 derivatives thereof with ascorbic acid.

7. The product obtained by the reaction of a sulfanil-N -alkylolamideand ascorbic acid, the acid radica1 being combined with the hydroxyl ofthe alkylol group.

8. The product obtained by the reaction of sulfanil-ethanolamide andascorbic acid, the acid radical being combined with the hydroxyl of theethanol group. p

9. The product obtained by the reaction of a sulfanil-N -alkylolamidewith ascorbic acid in an amount sufficient to react with the hydroxyl ofthe alkylol group and to add a molecule of ascorbic acid at thepara-amino group.

10. The product obtained by the reaction of sulfanil-N -ethanolamidewith ascorbic acid in an amount suflicient to react with the hydroxyl ofthe ethanol group and to add a molecule of ascorbic acid at thepara-amino group.

' SIMON L. RUSKIN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,212,831 Hofimann Aug. 27, 19402,275,809 Roberts Mar. 10, 1942 2,249,903 Lautenschlager July 22, 19412,140,989 Eisenbrand Dec. 20, 1938 2,132,662 Volwiler Oct. 11, 19382,134,246 Elger Oct. 25, 1938 2,150,140 Warnat Mar. 7, 1939 2,260,870Ruskin Oct. 28, 1941 2,294,937 Ruskin Sept. 8, 1942 2,283,817 Martin May19, 1942 OTHER REFERENCES Science, volume 86, pages 228, 229 (1937),cited in Chemical Abstracts 1937, page 8029.

